pyrimidinones and Prostatic-Neoplasms

Androgen deprivation therapy (ADT) is an integral component in the management of prostate cancer across multiple disease states. Traditionally, luteinizing hormone-releasing hormone (LHRH) agonists constituted the backbone of ADT. However, gonadotropin-releasing hormone receptor hormone (GnRH) antagonists also are available, which offer faster testosterone suppression and reduced likelihood of ADT-related adverse effects compared with LHRH agonists, including the potential for fewer ADT-associated major cardiac events. Until recently, all forms of LHRH agonists and GnRH antagonist formulations were of parenteral administration. However, recently relugolix gained Food and Drug Administration approval as the first oral GnRH antagonist. Relugolix achieves faster and more complete testosterone suppression compared with an LHRH agonist. This translates to more rapid prostate-specific antigen response compared with LHRH agonists. After discontinuation of relugolix, testosterone recovers faster than after GnRH agonists or injectable GnRH antagonist therapy. Overall, these factors provide opportunities for more precisely defined ADT duration when combined with radiation therapy. The rapid onset and offset of testosterone suppression with relugolix may require physicians to rethink the mechanism and goals of ADT when prescribing. As an oral formulation, relugolix enables patients to avoid pain and injection site reactions, limit extra office visits for injections, and achieve a shorter duration of experiencing the side effects of castrate testosterone levels. This convenience and tolerability may enhance physicians' willingness to prescribe ADT and patients' feeling of control during their ADT course, but the potential advantages are accompanied by the risks of patients choosing to discontinue therapy to escape side effects of ADT. This article focuses on different aspects of what is known and unknown regarding the optimal use of ADT and radiation therapy, and how relugolix, due to its properties, fit into our current treatment paradigms for localized prostate cancer.

Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Humans; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Testosterone

This is a summary of a research study (known as a clinical trial) called HERO. The HERO study compared how well relugolix and leuprolide worked in lowering blood testosterone to sustained castration levels in men with advanced prostate cancer. Sustained castration is a blood testosterone level below 50 ng/dl from Day 29 through 48 weeks of treatment.. Researchers looked at 930 adult men with advanced prostate cancer: 622 of these men took relugolix (by mouth once daily) and 308 received leuprolide (injected every 3 months). The HERO study showed that more men taking relugolix (97%) achieved sustained castration through 48 weeks than men receiving leuprolide (89%). This decrease in testosterone also happened more quickly in men taking relugolix. In 184 men who were followed up for 90 days after completing treatment, blood levels of testosterone returned to normal in more men who took relugolix than men who received leuprolide. Side effects were similar among men taking relugolix or receiving leuprolide, and most were identified as mild or moderate in terms of how bad they were.. In men with advanced prostate cancer and compared with those receiving leuprolide, more men taking relugolix had lower levels of blood testosterone. ClinicalTrials.gov NCT number: NCT03085095.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Humans; Ipilimumab; Language; Leuprolide; Male; Melanoma; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Testosterone

Relugolix is the first oral gonadotrophin-releasing hormone (GnRH) receptor antagonist. Based on the phase III HERO trial results, relugolix received Food and Drug Administration approval for adult patients with advanced prostate cancer (PCa).. We provide an overview of the preclinical and clinical development of relugolix and its role in the current treatment landscape of PCa.. Relugolix leads to rapid inhibition of testicular production of testosterone and its rapid recovery upon discontinuation. In the HERO trial, relugolix was associated with a superior cardiovascular safety profile compared to GnRH agonists. These attributes make relugolix a promising therapy for patients with preexisting cardiovascular comorbidities, those pursuing intermittent androgen deprivation therapy, and those who desire rapid testosterone recovery during 'off-treatment' periods. In the HERO trial, very few patients received concomitant enzalutamide (n = 17, 2.7%) or docetaxel (n < 10, 1.3%). Safety of relugolix has not been established in combination with many androgen-receptor-axis targeted therapies (e.g. abiraterone, apalutamide), cabazitaxel, or lutetium Lu 177 vipivotide tetraxetan, which precludes its use in combination with these agents. In addition, being an oral drug, relugolix may also be associated with challenges of affordability, adherence, and compliance in this predominantly elderly population.

Topics: Adult; Aged; Androgen Antagonists; Androgens; Clinical Trials, Phase III as Topic; Gonadotropin-Releasing Hormone; Humans; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Testosterone

Degarelix is associated with high rates of injection site reaction. The US Food and Drug Administration approved relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of advanced prostate cancer patients.. This systematic review and network meta-analysis aimed to compare the efficacy and safety of relugolix versus degarelix.. A systematic search was performed using major web databases for studies published before January 30, 2021, according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) extension statement for a network meta-analysis. Studies that compared the efficacy (12-mo castration rate with testosterone ≤50 ng/dl) and safety (adverse events [AEs]) of relugolix or degarelix and of the control group (GnRH agonists) were included. We used the Bayesian approach in the network meta-analysis.. Four studies (n = 2059) met our eligibility criteria. The main efficacy analysis was conducted for two different treatments (relugolix and all doses of degarelix vs GnRH agonists); relugolix (risk ratio [RR] 1.09, 95% credible interval [CrI]: 0.95-1.23) and degarelix (RR 0.98, 95% CrI: 0.91-1.06) were not associated with different 12-mo castration rates. In the subgroup analysis, degarelix 480 mg was significantly associated with a lower castration rate (RR 0.46, 95% CrI: 0.07-0.92). In all efficacy ranking analyses, relugolix achieved the best rank. The safety analyses showed that relugolix (RR 0.99, 95% CrI: 0.6-1.6 and RR 0.72, 95% CrI: 0.4-1.3, respectively) and degarelix (RR 1.1, 95% CrI: 0.75-1.35 and RR 1.05, 95% CrI: 0.42-2.6, respectively) were not associated with either all AE or serious AE rates. In the ranking analyses, degarelix achieved the worst rank of all AEs and the best rank of serious AEs. Relugolix (RR 0.44, 95% CrI: 0.16-1.2) and degarelix (RR 0.74, 95% CrI: 0.37-1.52) were not associated with different cardiovascular event (CVE) rates; both were associated with lower CVE rates than GnRH agonists in the ranking analyses.. We found that the efficacy and safety of relugolix are comparable with those of degarelix, albeit with no injection site reaction. Such data should be interpreted with caution until large-scale direct comparison studies with a longer follow-up are available.. We found that relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, has comparable efficacy and safety with degarelix, a parenteral GnRH antagonist, for the treatment of advanced prostate cancer patients.

Topics: Bayes Theorem; Gonadotropin-Releasing Hormone; Humans; Male; Network Meta-Analysis; Oligopeptides; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Randomized Controlled Trials as Topic; United States

Gonadotropin-releasing hormone (GnRH) receptor agonists are still the most commonly used androgen deprivation treatment (ADT) drugs for prostate cancer in clinical practice. Currently, the GnRH receptor antagonists used for endocrine therapy for prostate cancer primarily include degarelix and relugolix (TAK-385). The former is administered by subcutaneous injection, while the latter is an oral drug. Compared to GnRH agonists, GnRH antagonists reduce serum testosterone levels more rapidly without an initial testosterone surge or subsequent microsurges. This review focuses on the mechanism of action of GnRH antagonists and agonists, the developmental history of GnRH antagonists, and emerging data from clinical studies of the two antagonists used as endocrine therapy for prostate cancer.

Topics: Androgen Antagonists; Antineoplastic Agents; Humans; Male; Oligopeptides; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Receptors, LHRH

Present highlights from recent research examining the treatment of advanced prostate cancer.. Although debate remains about the optimal sequencing of docetaxel and novel androgen directed therapies in addition to androgen deprivation therapy (ADT) in the treatment of men with new metastatic prostate cancer, the novel LHRH antagonist relugolix seems poised to become an appealing option in a choice of initial ADT. Novel radioisotopes, genomically selected therapies, and immune therapy combinations show progress in opening up new treatment options for men with castration-resistant prostate cancer.. Although no clear consensus has emerged, evolving data continue to refine the selection of systemic therapies in treatment naïve metastatic prostate cancer. With potentially less cardiotoxic androgen deprivation therapies, novel radioisotopes, targeted pharmaceuticals, and immune therapy combinations, progress appears to be on the horizon in improving outcomes for men with advanced prostate cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Male; Neoplasm Metastasis; Phenylurea Compounds; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Pyrimidinones; Radiopharmaceuticals; Randomized Controlled Trials as Topic

Androgen deprivation therapy (ADT) comes in several forms, such as surgical castration or medical castration using gonadotropin-releasing hormone (GnRH) agonist or GnRH antagonist therapy. ADT is a critical treatment for high-risk and metastatic prostate cancer. There are important differences between GnRH agonists and antagonists. Here we review the mechanism of action between GnRH agonists and antagonists and the studies that led to the approval of degarelix. We also comment on the potential risks and benefits of degarelix, particularly when it comes to cardiovascular health. Finally, we describe an oral GnRH antagonist, which is not currently used in prostate cancer, but is included for completeness.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones

Recently, LHRH antagonists have been established in the management of advanced prostate cancer, although the vast majority of Medical Oncologists and Urologists still prefer the LHRH agonists. Areas Covered: In this article we assess the therapeutic outcomes and the safety of the LHRH antagonists (mainly degarelix) compared to the LHRH agonists. Expert Commentary: Relevant studies demonstrated that LHRH antagonists are at least non-inferior to the LHRH agonists regarding therapeutic efficacy and safety, while there is potential benefit over the LHRH agonists in terms of cardiovascular morbidity and disease control. Disadvantages regarding formulation and frequency of administration are currently seem to be improving, as a 3-month depot of degarelix is evaluated and relugolix, an investigational orally administered is undergoing phase I studies, while the results of relative comparative studies are warranted.

Topics: Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Male; Oligopeptides; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones

External beam radiotherapy (EBRT) with neoadjuvant/adjuvant androgen deprivation therapy (ADT) is an established treatment option to prolong survival for patients with intermediate- and high-risk prostate cancer (PCa). Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was evaluated in this clinical setting in comparison with degarelix, an injectable GnRH antagonist.. To evaluate the safety and efficacy of relugolix to achieve and maintain castration.. A phase 2 open-label study was conducted in 103 intermediate-risk PCa patients undergoing primary EBRT and neoadjuvant/adjuvant ADT between June 2014 and December 2015.. Patients randomly assigned (3:2) to 24-wk treatment with either daily oral relugolix or 4-wk subcutaneous depot degarelix (reference control).. The primary endpoint was the rate of effective castration (testosterone <1.73nmol/l) in relugolix patients between 4 and 24 wk of treatment. Secondary endpoints included rate of profound castration (testosterone <0.7nmol/l), prostate-specific antigen (PSA) levels, prostate volume, quality of life (QoL) assessed using the Aging Males' Symptoms scale, and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (30-item EORTC core questionnaire [EORTC QLQ-C30] and 25-item EORTC prostate cancer module [EORTC QLQ-PR25]) questionnaires, and safety. No formal statistical comparisons with degarelix were planned.. Castration rates during treatment were 95% and 82% with relugolix and 89% and 68% with degarelix for 1.73 and 0.7nmol/l thresholds, respectively. Median time to castration in the relugolix arm was 4 d. During treatment, PSA levels and prostate volumes were reduced in both groups. Three months after discontinuing treatment, 52% of men on relugolix and 16% on degarelix experienced testosterone recovery (statistical significance of differences not tested). Mean and median QoL scores improved following treatment discontinuation. The most common adverse event was hot flush (relugolix 57%; degarelix 61%). Lack of blinding was a potential limitation.. Relugolix achieved testosterone suppression to castrate levels within days and maintained it over 24 wk with a safety profile consistent with its mechanism of action.. Oral once-daily relugolix may be a novel oral alternative to injectable androgen deprivation therapies.

Topics: Administration, Oral; Aged; Gonadotropin-Releasing Hormone; Humans; Male; Neoadjuvant Therapy; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Risk Assessment

Injectable luteinizing hormone-releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known.. In this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients.. A total of 622 patients received relugolix and 308 received leuprolide. Of men who received relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88).. In this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.).

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Cardiovascular Diseases; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Testosterone

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Humans; Kallikreins; Male; Phenylurea Compounds; Prostate-Specific Antigen; Prostatic Neoplasms; Pyrimidinones; Receptors, LHRH; Testosterone

TAK-385 is a highly selective, oral, nonpeptide GnRH antagonist being investigated as a possible prostate cancer treatment.. The objectives were to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-385 on LH and testosterone.. This was a three-part, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study in 176 healthy male UK volunteers.. Part 1, single doses of TAK-385 (0 [placebo], 80, 120, 180, or 360 mg). Part 2, 14-day TAK-385 (0, 20, 40, 80, or 180 mg) daily. Part 3, 28-day TAK-385 (40 [with loading dose], 60, 80, or 160 mg) or placebo daily. Parts 2 and 3 included men aged 40-75 years.. Main outcome measures included plasma concentrations of TAK-385, LH, and testosterone.. Oral TAK-385 was readily absorbed, and steady state was reached in ≤ 14 days. Food reduced TAK-385 systemic exposure by 47-52%. Mean serum testosterone levels declined ≤ 6 hours after TAK-385 administration. Loading doses up to 360 mg on day 1 or 360 mg on day 1 followed by 240 mg on day 2 reduced the time to achieve castrate testosterone levels from ≥ 7 to <3 days. TAK-385 doses ≥ 80 mg/d achieved sustained medical castration and trough TAK-385 concentrations >4 ng/mL. After discontinuation of TAK-385 on day 28, testosterone levels normalized in most subjects in ≤ 28 days. Common adverse events included bradycardia, headache, and hot flush (all grade ≤ 2).. Oral TAK-385 (40-180 mg/d) was well tolerated and effectively lowered testosterone in healthy men. Planned phase 2 doses in men with hormone-sensitive prostate cancer are 80 and 120 mg/d.

Topics: Adult; Aged; Castration; Dose-Response Relationship, Drug; Double-Blind Method; Food-Drug Interactions; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Testosterone; Treatment Outcome; Young Adult

We highlight concerns regarding the approval of relugolix for patients with prostate cancer. These include the unsuitable comparator arm and primary endpoint in the HERO trial, as well as potential selection bias and the poor representativeness of the trial population. Dosing adherence to a daily tablet may also be an issue in comparison to injections at 3-mo intervals. Rigorous postmarketing trials of relugolix assessing clinically meaningful endpoints for these patients are needed.

Topics: Humans; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; United States; United States Food and Drug Administration

Androgen deprivation therapy (ADT) has been a mainstay of prostate cancer treatment for decades. Relugolix was FDA-approved in 2020 and is currently the only ADT option via an oral route. While the opportunity to use an oral medication for this indication has some advantages, a balanced discussion is required to understand in what clinical settings this agent truly has benefit over long-acting injectable formulations of ADT. Furthermore, patient preference, compliance, financial toxicity, and perhaps most importantly, pharmacologic characteristics must be considered.

Topics: Androgen Antagonists; Humans; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones

Topics: Humans; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Testosterone

Prostate cancer is among the most common cancer diagnoses in men, and the best treatment for patients with metastatic disease in advanced stages is still unclear. Previously, we have demonstrated that the three 1-(3-(aryl-4,5-dihydroisoxazol-5-yl)methyl)-4-trihalomethyl-1H-pyrimidin-2- ones derivatives (8a, 8e and 9c) present important cytotoxicity and selectivity for tumoral cells. Considering that various cytotoxic drugs have been assessed in patients with prostate cancer, but few drugs show survival advantage, we decided to study these three compounds (8a, 8e and 9c) in prostate cancer cells, androgen receptor (AR)-positive 22Rv-1 and AR-negative PC-3 cells. We obtained the half maximal inhibitory concentration (IC50) of 8a, 8e and 9c in prostate cancer cells and based on high selectivity of 9c to PC-3 cells, we determined the mechanism of this compound to induce cell death through different methods. We show here that 9c compound induces cell cycle arrest in G2/M, increasing the levels of reactive oxygen species and DNA damage, and triggers DNA damage response by ataxia-telangiectasia mutated (ATM) and histone H2AX phosphorylation induction. The compound also led PC-3 to lipid peroxidation and mitochondrial depolarization which triggered the activation of intrinsic pathway, confirmed by increase of cleaved caspase-9 and 3. In this work we also show the ability of 9c in reducing vascular endothelial growth factor expression (VEGF) and inhibiting topoisomerase I enzyme, therefore indicating a potential new molecule to be further investigated for prostate cancer management.

Topics: Angiogenesis Inhibitors; Apoptosis; Ataxia Telangiectasia Mutated Proteins; DNA Damage; Down-Regulation; G2 Phase Cell Cycle Checkpoints; Histones; Humans; Lipid Peroxidation; Male; Membrane Potential, Mitochondrial; Mitochondria; Neovascularization, Pathologic; PC-3 Cells; Phosphorylation; Prostatic Neoplasms; Pyrimidinones; Reactive Oxygen Species; Signal Transduction; Topoisomerase I Inhibitors; Vascular Endothelial Growth Factor A

Relugolix (Orgovyx) has been approved for the treatment of advanced prostate cancer. It is the first oral gonadotropin-releasing hormone receptor antagonist.As with other androgen deprivation therapy, there is a risk of prolonging the QT or QTc interval with relugolix. The drug may also cause embryo-fetal toxicity.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Middle Aged; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones

Topics: Androgen Antagonists; Androgens; Humans; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones

Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) analogues is standard treatment for intermediate and advanced prostate cancer. GnRH agonist therapy results in an initial testosterone flare, and increased metabolic and cardiovascular risks. The GnRH antagonist relugolix is able to reduce serum testosterone levels in men with prostate cancer without inducing testosterone flare. In the HERO Phase III trial, relugolix was superior to leuprolide acetate at rapidly reducing testosterone and continuously suppressing testosterone, with faster post-treatment recovery of testosterone levels. Relugolix was associated with a 54% lower incidence of major adverse cardiovascular events than leuprolide acetate. As the first oral GnRH antagonist approved for the treatment of advanced prostate cancer, relugolix offers a new treatment option.. Lay abstract The male sex hormone testosterone promotes the growth of prostate cancer cells. Some drug treatments for prostate cancer, such as gonadotropin-releasing hormone (GnRH) receptor agonists and antagonists, work to reduce the production of testosterone. However, GnRH receptor agonists like leuprolide acetate can increase testosterone levels at first, before reducing it, and this temporary increase can cause side effects, such as bone pain. Drugs of this type have also been linked to a higher risk of heart attacks, strokes, and death. Relugolix works a different way; it is a GnRH receptor antagonist that reduces testosterone without an initial increase. A clinical study showed that relugolix reduced testosterone levels more quickly than leuprolide acetate, a commonly used injectable drug for the treatment of prostate cancer. After stopping treatment, levels of testosterone in the blood returned to normal faster in men who received relugolix than in men who received leuprolide acetate. Men who received relugolix had a lower incidence of heart attacks, strokes, and death compared with men who received leuprolide acetate. The US FDA approved relugolix as the first oral, once-daily GnRH receptor antagonist for the treatment of advanced prostate cancer, offering men a new treatment option.

Topics: Cardiovascular Diseases; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Gonadotropin-Releasing Hormone; Humans; Incidence; Leuprolide; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Randomized Controlled Trials as Topic; Testosterone; Treatment Outcome

Emerging data indicate that the reverse transcriptase (RT) protein encoded by LINE-1 transposable elements is a promising cancer target. Nonnucleoside RT inhibitors, e.g. efavirenz (EFV) and SPV122.2, reduce proliferation and promote differentiation of cancer cells, concomitant with a global reprogramming of the transcription profile. Both inhibitors have therapeutic anticancer efficacy in animal models. Here we have sought to clarify the mechanisms of RT inhibitors in cancer cells. We report that exposure of PC3 metastatic prostate carcinoma cells to both RT inhibitors results in decreased proliferation, and concomitantly induces genome damage. This is associated with rearrangements of the nuclear architecture, particularly at peripheral chromatin, disruption of the nuclear lamina, and budding of micronuclei. These changes are reversible upon discontinuation of the RT-inhibitory treatment, with reconsititution of the lamina and resumption of the cancer cell original features. The use of pharmacological autophagy inhibitors proves that autophagy is largely responsible for the antiproliferative effect of RT inhibitors. These alterations are not induced in non-cancer cell lines exposed to RT inhibitors. These data provide novel insight in the molecular pathways targeted by RT inhibitors in cancer cells.

Topics: Alkynes; Autophagy; Benzoxazines; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cyclopropanes; DNA Damage; Humans; Male; PC-3 Cells; Prostatic Neoplasms; Pyrimidinones; Reverse Transcriptase Inhibitors

Topics: Androgen Antagonists; Androgens; Humans; Male; Neoadjuvant Therapy; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Receptors, LHRH

Prostate cancer (PC) care is rapidly evolving, with improved treatment options and outcomes. Trials recently published in the New England Journal of Medicine report on an oral lutenizing-hormone-releasing hormone antagonist with superior endocrine and tolerability profiles and positive outcomes for non-metastatic PC with androgen receptor antagonists, respectively.

Topics: Androgen Antagonists; Androgens; Humans; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones

Results from the phase 3 HERO trial(NCT03085095), presented during the 2020 American Society of Clinical Oncology Virtual Scientific Program, indicated that relugolix (Relumina) demonstrated superiority over leuprolide (Lupron) in sustained testosterone suppression through 48 weeks, fast testosterone recovery after discontinuation, and a 50% reduction in major adverse cardiovascular events (MACE) in patients with advanced prostate cancer.

Topics: Antineoplastic Agents, Hormonal; Clinical Trials, Phase III as Topic; Humans; Leuprolide; Male; Multicenter Studies as Topic; Neoplasm Staging; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Randomized Controlled Trials as Topic; Receptors, LHRH; Testosterone

Topics: Androgen Antagonists; Androgens; Humans; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones

Topics: Androgen Antagonists; Androgens; Humans; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones

The orally active nonpeptide gonadotropin-releasing hormone (GnRH)-receptor antagonist relugolix (Relumina) is being developed by Takeda and ASKA Pharmaceutical as a treatment for various sex hormone related disorders. Relugolix was recently approved for marketing in Japan as a treatment for symptoms associated with uterine fibroids, and studies evaluating the efficacy of the drug as treatment for endometriosis-associated pain and prostate cancer are currently underway. This article summarizes the milestones in the development of relugolix leading to this first approval for the treatment of symptoms associated with uterine fibroids.

Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Drug Approval; Endometriosis; Female; Hormone Antagonists; Humans; Japan; Leiomyoma; Male; Middle Aged; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Receptors, LHRH; Treatment Outcome

Epigenetic alteration plays a major role in the development and progression of human cancers, including prostate cancer. Histones are the key factors in modulating gene accessibility to transcription factors and post-translational modification of the histone N-terminal tail including methylation is associated with either transcriptional activation (H3K4me2) or repression (H3K9me3). Furthermore, phosphoinositide 3-kinase (PI3 K) signaling and the androgen receptor (AR) are the key determinants in prostate cancer development and progression. We recently showed that prostate-targeted nano-micelles loaded with PI3 K/p110beta specific inhibitor TGX221 blocked prostate cancer growth in vitro and in vivo. Our objective of this study was to determine the role of PI3 K signaling in histone methylation in prostate cancer, with emphasis on histone H3K4 methylation.. PI3 K non-specific inhibitor LY294002 and p110beta-specific inhibitor TGX221 were used to block PI3 K/p110beta signaling. The global levels of H3K4 and H3K9 methylation in prostate cancer cells and tissue specimens were evaluated by Western blot assay and immunohistochemical staining. A synthetic androgen R1881 was used to stimulate AR activity in prostate cancer cells. A castration-resistant prostate cancer (CRPC) specific human tissue microarray (TMA) was used to assess the global levels of H3K4me2 methylation by immunostaining approach.. Our data revealed that H3K4me2 levels were significantly elevated after androgen stimulation. With RNA silencing and pharmacology approaches, we further defined that inhibition of PI3 K/p110beta activity through gene-specific knocking down and small chemical inhibitor TGX221 abolished androgen-stimulated H3K4me2 methylation. Consistently, prostate cancer-targeted delivery of TGX221 in vivo dramatically reduced the global levels of H3K4me2 as assessed by immunohistochemical staining on tissue section of mouse xenografts from CRPC cell lines 22RV1 and C4-2. Finally, immunostaining data revealed a strong H3K4me2 immunosignal in CRPC tissues compared to primary tumors and benign prostate tissues.. Taken together, our results suggest that PI3 K/p110beta-dependent signaling is involved in androgen-stimulated H3K4me2 methylation in prostate cancer, which might be used as a novel biomarker for disease prognosis and targeted therapy. Prostate 77:299-308, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Histones; Humans; Male; Methylation; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Prostatic Neoplasms; Pyrimidinones

Combination of androgen ablation along with early detection and surgery has made prostate cancer highly treatable at the initial stage. However, this cancer remains the second leading cause of cancer death among American men due to castration-resistant progression, suggesting that novel therapeutic agents are urgently needed for this life-threatening condition. Phosphatidylinositol 3-kinase p110β is a major cellular signaling molecule and has been identified as a critical factor in prostate cancer progression. In a recent report, we established a nanomicelle-based strategy to deliver p110β-specific inhibitor TGX221 to prostate cancer cells by conjugating the surface of nanomicelles with a RNA aptamer against prostate specific membrane antigen (PSMA) present in all clinical prostate cancers. In this study, we tested this nanomicellar TGX221 for its in vivo anti-tumor effect in mouse xenograft models.. Prostate cancer cell lines LAPC-4, LNCaP, C4-2 and 22RV1 were used to establish subcutaneous xenograft tumors in nude mice. Paraffin sections from xenograft tumor specimens were used in immunohistochemistry assays to detect AKT phosphorylation, cell proliferation marker Ki67 and proliferating cell nuclear antigen (PCNA), as well as 5-bromo-2-deoxyuridine (BrdU) incorporation. Quantitative PCR assay was conducted to determine prostate-specific antigen (PSA) gene expression in xenograft tumors.. Although systemic delivery of unconjugated TGX221 significantly reduced xenograft tumor growth in nude mice compared to solvent control, the nanomicellar TGX221 conjugates completely blocked tumor growth of xenografts derived from multiple prostate cancer cell lines. Further analyses revealed that AKT phosphorylation and cell proliferation indexes were dramatically reduced in xenograft tumors received nanomicellar TGX221 compared to xenograft tumors received unconjugated TGX221 treatment. There was no noticeable side effect by gross observation or at microscopic level of organ tissue section.. These data strongly suggest that prostate cancer cell-targeted nanomicellar TGX221 is an effective anti-cancer agent for prostate cancer.

Topics: Animals; Antigens, Surface; Apoptosis; Cell Line, Tumor; Cell Proliferation; Female; Glutamate Carboxypeptidase II; Humans; Male; Mice; Mice, Nude; Morpholines; Neoplasm Transplantation; Phosphoinositide-3 Kinase Inhibitors; Prostate-Specific Antigen; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Pyrimidinones; Transplantation, Heterologous

4,6-diarylpyrimidones as constrained chalcone analogues have been synthesised in the present study. The synthesised compounds were evaluated against a panel of human cancer cell lines. Striking selectivity was displayed by the compounds against MiaPaCa (Pancreatic) cell lines while PC-3 (prostate) and A-549 (lung) cell lines were almost resistant to the exposure of the test compounds. Compound SK - 25 exhibited remarkable cytotoxicity against MiaPaca-2 cell line with an IC50 value of 1.95 µM and was found to induce apoptosis evidenced through phase contrast microscopy, DAPI staining and mitochondrial membrane potential loss. The cell phase distribution studies indicated that the apoptotic population increased from 1.79% in control sample to 30.33 % in sample treated with 20 µM compound SK-25.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chalcone; HCT116 Cells; Humans; Lung Neoplasms; Male; Membrane Potential, Mitochondrial; Prostatic Neoplasms; Pyrimidinones

Aberrant expression of cell cycle regulators have been implicated in prostate cancer development and progression. Therefore, understanding transcriptional networks controlling the cell cycle remain a challenge in the development of prostate cancer treatment. In this study, we found that icilin, a super-cooling agent, down-regulated the expression of cell cycle signature genes and caused G1 arrest in PC-3 prostate cancer cells. With reverse-engineering and an unbiased interrogation of a prostate cancer-specific regulatory network, master regulator analysis discovered that icilin affected cell cycle-related transcriptional modules and identified E2F1 transcription factor as a target master regulator of icilin. Experimental analyses confirmed that icilin reduced the activity and expression levels of E2F1. These results demonstrated that icilin inactivates a small regulatory module controlling the cell cycle in prostate cancer cells. Our study might provide insight into the development of cell cycle-targeted cancer therapeutics.

Topics: Cell Cycle; Cell Line, Tumor; DNA, Superhelical; E2F1 Transcription Factor; Humans; Male; Prostatic Neoplasms; Pyrimidinones

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit. Recent studies showed that TGX-221 has antiproliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles was significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than that of the naked drug, and the drug clearance rate was 6.16-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Drug Delivery Systems; Humans; Male; Mice; Mice, Nude; Micelles; Morpholines; Polyesters; Polyethylene Glycols; Prodrugs; Prostatic Neoplasms; Pyrimidinones

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.

Topics: Anilides; Animals; Antineoplastic Agents; Cell Line, Tumor; Class Ia Phosphatidylinositol 3-Kinase; Crystallography, X-Ray; Female; Gene Deletion; Humans; Male; Mice; Mice, SCID; Models, Molecular; Phosphoinositide-3 Kinase Inhibitors; Prostate; Prostatic Neoplasms; Protein Isoforms; PTEN Phosphohydrolase; Pyrimidinones; Structure-Activity Relationship

Overexpression of the cation-permeable channel TRPM8 in prostate cancers might represent a novel opportunity for their treatment. Inhibitors of TRPM8 reduce the growth of prostate cancer cells. We have used two recently described and highly specific blockers, AMTB and JNJ41876666, and RNAi to determine the relevance of TRPM8 expression in the proliferation of non-tumor and tumor cells. Inhibition of the expression or function of the channel reduces proliferation rates and proliferative fraction in all tumor cells tested, but not of non-tumor prostate cells. We observed no consistent acceleration of growth after stimulation of the channel with menthol or icilin, indicating that basal TRPM8 expression is enough to sustain growth of prostate cancer cells.

Topics: Benzamides; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Proliferation; Humans; Ion Channels; Male; Menthol; Prostate; Prostatic Neoplasms; Pyrimidinones; Thiophenes; Transfection; TRPM Cation Channels; Wound Healing

Prostate cancer (PC) is a major health problem in adult males. TRPM8, a cationic TRP channel activated by cooling and menthol is upregulated in PC. However, the precise role of TRPM8 in PC is still unclear. Some studies hypothesized that TRPM8-mediated transmembrane Ca(2+) fluxes play a key role in cellular proliferation of PC cells. In contrast, other findings suggest that high TRPM8 levels may reduce the metastatic potential of PC cells. A detailed understanding of the response of TRPM8 channels to pharmacological modulators of their activity is relevant when considering potential therapies, targeting this ion channel to treat PC. We characterized the pharmacological and functional properties of native TRPM8 channels in four human prostate cell lines, PNT1A, LNCaP, DU145, and PC3, commonly used as experimental models of PC. PNT1A is a non-tumoral prostate cell line while the other three correspond to different stages of PC. Here, we show that cold- and agonist-evoked [Ca(2+)](i) responses in PC cells are much less sensitive to well-characterized agonists (menthol and icilin) and antagonists (BCTC, clotrimazole, and DD01050) of TRPM8 channels, compared to TRPM8 channels in other tissues, suggesting a different molecular composition and/or spatial organization. In addition, the forced overexpression of human TRPM8 facilitated the trafficking of TRPM8 channels residing in the endoplasmic reticulum to the plasma membrane, leading to a marked potentiation in the efficacy of the different blockers. These results predict that blockers of canonical TRPM8 channels may be less effective in halting proliferation of PC cells than expected.

Topics: Arginine; Calcium; Cell Line; Cell Line, Tumor; Cell Membrane; Clotrimazole; Cold Temperature; Endoplasmic Reticulum; Glycine; Humans; Male; Menthol; Prostate; Prostatic Neoplasms; Pyrazines; Pyridines; Pyrimidinones; TRPM Cation Channels

Aberrant regulation of cell cycle confers a limitless replicative potential, which is a hallmark of cancer. Currently, the compounds targeting the cell cycle are undergoing cancer clinical trials. In this study, we demonstrated that icilin, a cooling compound, induces G1 arrest in PC-3 prostate cancer cells without cell death. Icilin modulated the expression level of various cell cycle regulators at transcription or post-translational levels. In addition, icilin activated JNK and p38 kinase pathways, but not ERK. Both JNK and p38 kinases cooperatively mediated icilin-induced G1 arrest, which was rescued by pharmacologic inhibition of these kinases. The action of icilin on G1 arrest was unrelated to the activation of TRPM8 calcium channel. Our findings suggest that icilin is a valuable chemical probe for future investigation aiming at delineating the molecular mechanisms of cell cycle regulation in prostate cancer.

Topics: Cell Line, Tumor; Enzyme Activation; G1 Phase; Humans; Male; MAP Kinase Kinase 4; p38 Mitogen-Activated Protein Kinases; Prostatic Neoplasms; Pyrimidinones; TRPM Cation Channels

TGX-221 is a highly potent phosphoinositide 3-kinase β (PI3Kβ) inhibitor that holds great promise as a novel chemotherapeutic agent to treat prostate cancer. However, poor solubility and lack of targetability limit its therapeutic applications. The objective of this present study is to develop a peptide-drug conjugate to specifically deliver TGX-221 to HER2 overexpressing prostate cancer cells. Four TGX-221 derivatives with added hydroxyl groups were synthesized for peptide conjugation. Among them, TGX-D1 exhibited a similar bioactivity to TGX-221, and it was selected for conjugation with a peptide promoiety containing a HER2-targeting ligand and a prostate specific antigen (PSA) substrate linkage. From this selection, the peptide-drug conjugate was proven to be gradually cleaved by PSA to release TGX-D1. Cellular uptake of the peptide-drug conjugate was significantly higher in prostate cancer cells compared to the parent drug. Moreover, both the peptide-drug conjugate and its cleaved products demonstrated comparable activities as the parent drug TGX-D1. Our results suggest that this peptide-drug conjugate may provide a promising chemotherapy for prostate cancer patients.

Topics: Androgens; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chromatography, Liquid; Drug Stability; Humans; Male; Morpholines; Peptides; Prodrugs; Prostate-Specific Antigen; Prostatic Neoplasms; Pyrimidinones; Receptor, ErbB-2; Tandem Mass Spectrometry

Radiotherapy is commonly used to treat a variety of solid tumors. However, improvements in the therapeutic ratio for several disease sites are sorely needed, leading us to assess molecularly targeted therapeutics as radiosensitizers. The aim of this study was to assess the wee1 kinase inhibitor, MK-1775, for its ability to radiosensitize human tumor cells.. Human tumor cells derived from lung, breast, and prostate cancers were tested for radiosensitization by MK-1775 using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of MK-1775 to abrogate the radiation-induced G₂ block, thereby allowing cells harboring DNA lesions to prematurely progress into mitosis, was determined using flow cytometry and detection of γ-H2AX foci. The in vivo efficacy of the combination of MK-1775 and radiation was assessed by tumor growth delay experiments using a human lung cancer cell line growing as a xenograft tumor in nude mice.. Clonogenic survival analyses indicated that nanomolar concentrations of MK-1775 radiosensitized p53-defective human lung, breast, and prostate cancer cells but not similar lines with wild-type p53. Consistent with its ability to radiosensitize, MK-1775 abrogated the radiation-induced G₂ block in p53-defective cells but not in p53 wild-type lines. MK-1775 also significantly enhanced the antitumor efficacy of radiation in vivo as shown in tumor growth delay studies, again for p53-defective tumors.. These results indicate that p53-defective human tumor cells are significantly radiosensitized by the potent and selective wee1 kinase inhibitor, MK-1775, in both the in vitro and in vivo settings. Taken together, our findings strongly support the clinical evaluation of MK-1775 in combination with radiation.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Combined Modality Therapy; Female; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Neoplasms; Nuclear Proteins; Prostatic Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Radiation-Sensitizing Agents; Transplantation, Heterologous; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

The purpose of this study was to further characterize cell growth-inhibitory effects of a recently identified androgen receptor (AR) signaling inhibitor 6-amino-2-[2-(4-tert-butyl-pnenoxy)-ethylsulfanyl]-1H-pyrimidin-4-one (DL3)(5) and antiandrogen bicalutamide (Bic). DL3 was more potent than Bic in induction of G1 arrest and reduction of G1-related cell cycle protein expression in AR-positive LNCaP cells. DL3, but not Bic, moderately inhibited growth of AR-negative PC-3 cells independent of G1 arrest. The data indicated that DL3 inhibit cell growth in both AR-dependent and -independent manners and is potentially a potent therapeutic agent for the management of advanced human prostate cancer.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Anilides; Apoptosis; Blotting, Western; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cyclin D; Cyclin-Dependent Kinases; Dose-Response Relationship, Drug; G1 Phase; Humans; Male; Nitriles; Phosphorylation; Prostatic Neoplasms; Pyrimidinones; Receptors, Androgen; Signal Transduction; Sulfides; Tosyl Compounds

One of the best-studied temperature-gated channels is transient receptor potential melastatin 8 (TRPM8), which is activated by cold and cooling agents, such as menthol. Besides inducing a cooling sensation in sensory neurons, TRPM8 channel activation also plays a major role in physiopathology. Indeed, TRPMP8 expression increases in early stages of prostate cancer and its involvement in prostate cell apoptosis has recently been demonstrated. Thus, as TRPM8 is a tumor marker with significant potential use in diagnosis, as well as a target for cancer therapy, there is a need for new TRPM8-specific ligands. In this study, we investigated the action of "WS" compounds on TRPM8 channels. We compared the affinity of these molecules to that of menthol and icilin. This enabled us to identify new TRPM8 agonists. The menthol analog with the highest affinity, WS-12, had an EC(50) value about 2000 times lower than that of menthol and is, therefore, the highest-affinity TRPM8 ligand known to date. Finally, incorporating a fluorine atom in the WS-12 retained 75% of the activity of the parent compound. The high affinity of this new TRPM8 ligand and the possibility of incorporating a radiohalogen could thus be useful for diagnosis, monitoring and, perhaps, even therapy of prostate cancer.

Topics: Animals; Antineoplastic Agents; Antipruritics; Biomarkers, Tumor; Cell Line, Tumor; Diagnostic Imaging; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Ligands; Male; Menthol; Prostatic Neoplasms; Pyrimidinones; TRPM Cation Channels